Bottom Line:
The median number of nerves, the median area of neural tissue, and the median nerve diameter per 10 mm(2) were larger in the hyperglycemia group than those in the euglycemia group (p = 0.007, p = 0.009, and p = 0.004, respectively).The integrated optical density (IOD) of MPP staining was lower in the hyperglycemia group than those in the euglycemia group (p = 0.019), while the expression levels of NGF and p75 were higher in the hyperglycemia group than those in the euglycemia group (p = 0.002, and p = 0.026, respectively).The abnormal expression of NGF and p75 may also be involved in this process and subsequently lead to a lower rate of curative surgery.

Background: Patients with higher levels of fasting serum glucose have higher death rates from pancreatic cancer compared to patients with lower levels of fasting serum glucose. However, the reasons have not been studied. The goal of the current study was to examine the neural alterations in pancreatic cancer patients with hyperglycemia and to identify the relationship between the neural alterations and perineural invasion.

Methodology/principal findings: The clinical and pathological features of 61 formalin-fixed pancreatic cancer specimens and 10 normal pancreases as controls were analyzed. Furthermore, the expression of Protein Gene Product 9.5 (PGP9.5), Myelin P0 protein (MPP), NGF, TrkA, and p75 were examined by immunohistochemistry. The median number of nerves, the median area of neural tissue, and the median nerve diameter per 10 mm(2) were larger in the hyperglycemia group than those in the euglycemia group (p = 0.007, p = 0.009, and p = 0.004, respectively). The integrated optical density (IOD) of MPP staining was lower in the hyperglycemia group than those in the euglycemia group (p = 0.019), while the expression levels of NGF and p75 were higher in the hyperglycemia group than those in the euglycemia group (p = 0.002, and p = 0.026, respectively). The nerve bundle invasion of pancreatic cancer was more frequent in the hyperglycemia group than in the euglycemia group (p = 0.000).

Conclusions/significance: Nerve damage and regeneration occur simultaneously in the tumor microenvironment of pancreatic cancer patients with hyperglycemia; the simultaneous occurrence may aggravate the process of perineural invasion. The abnormal expression of NGF and p75 may also be involved in this process and subsequently lead to a lower rate of curative surgery.

pone-0017385-g002: Myelin sheath immunostaining in different group.MPP immunostaining of pancreatic cancer tissue in the euglycemia group (A, B, arrowhead) and hyperglycemia group (C, D, arrowhead). The left panel shows an original magnification of 100×, and the right panel an original magnification of 400×. The frequency of moderate to strong MPP staining of nerves was significantly lower in the hyperglycemia group than in the euglycemia group. Figure arrowheads indicate the immunostainings.

Mentions:
The immunostaining of the neuron specific protein PGP9.5 was localized to the nerve fibers of pancreatic tissues (Fig. 1). The number of immunostainings represents the number and area of pancreatic nerve. The immunostaining of MPP which guides the wrapping process and ultimately compacts adjacent lamellae, was localized to the membrane of Schwann cells (Fig. 2). MPP expression in the nerves was significantly lower (p = 0.019) in the hyperglycemia group than in the euglycemia group, indicating dysfunction or demyelination of the myelin sheath. As shown in Table 2, the median area and median number of nerves per 10 mm2 of tissue area were significantly higher in the hyperglycemia group than in the euglycemia group (p = 0.007, p = 0.009, respectively). The median nerve area and median nerve diameter (p = 0.004) were significantly higher in the hyperglycemia group than in the euglycemia group.

pone-0017385-g002: Myelin sheath immunostaining in different group.MPP immunostaining of pancreatic cancer tissue in the euglycemia group (A, B, arrowhead) and hyperglycemia group (C, D, arrowhead). The left panel shows an original magnification of 100×, and the right panel an original magnification of 400×. The frequency of moderate to strong MPP staining of nerves was significantly lower in the hyperglycemia group than in the euglycemia group. Figure arrowheads indicate the immunostainings.

Mentions:
The immunostaining of the neuron specific protein PGP9.5 was localized to the nerve fibers of pancreatic tissues (Fig. 1). The number of immunostainings represents the number and area of pancreatic nerve. The immunostaining of MPP which guides the wrapping process and ultimately compacts adjacent lamellae, was localized to the membrane of Schwann cells (Fig. 2). MPP expression in the nerves was significantly lower (p = 0.019) in the hyperglycemia group than in the euglycemia group, indicating dysfunction or demyelination of the myelin sheath. As shown in Table 2, the median area and median number of nerves per 10 mm2 of tissue area were significantly higher in the hyperglycemia group than in the euglycemia group (p = 0.007, p = 0.009, respectively). The median nerve area and median nerve diameter (p = 0.004) were significantly higher in the hyperglycemia group than in the euglycemia group.

Bottom Line:
The median number of nerves, the median area of neural tissue, and the median nerve diameter per 10 mm(2) were larger in the hyperglycemia group than those in the euglycemia group (p = 0.007, p = 0.009, and p = 0.004, respectively).The integrated optical density (IOD) of MPP staining was lower in the hyperglycemia group than those in the euglycemia group (p = 0.019), while the expression levels of NGF and p75 were higher in the hyperglycemia group than those in the euglycemia group (p = 0.002, and p = 0.026, respectively).The abnormal expression of NGF and p75 may also be involved in this process and subsequently lead to a lower rate of curative surgery.

Background: Patients with higher levels of fasting serum glucose have higher death rates from pancreatic cancer compared to patients with lower levels of fasting serum glucose. However, the reasons have not been studied. The goal of the current study was to examine the neural alterations in pancreatic cancer patients with hyperglycemia and to identify the relationship between the neural alterations and perineural invasion.

Methodology/principal findings: The clinical and pathological features of 61 formalin-fixed pancreatic cancer specimens and 10 normal pancreases as controls were analyzed. Furthermore, the expression of Protein Gene Product 9.5 (PGP9.5), Myelin P0 protein (MPP), NGF, TrkA, and p75 were examined by immunohistochemistry. The median number of nerves, the median area of neural tissue, and the median nerve diameter per 10 mm(2) were larger in the hyperglycemia group than those in the euglycemia group (p = 0.007, p = 0.009, and p = 0.004, respectively). The integrated optical density (IOD) of MPP staining was lower in the hyperglycemia group than those in the euglycemia group (p = 0.019), while the expression levels of NGF and p75 were higher in the hyperglycemia group than those in the euglycemia group (p = 0.002, and p = 0.026, respectively). The nerve bundle invasion of pancreatic cancer was more frequent in the hyperglycemia group than in the euglycemia group (p = 0.000).

Conclusions/significance: Nerve damage and regeneration occur simultaneously in the tumor microenvironment of pancreatic cancer patients with hyperglycemia; the simultaneous occurrence may aggravate the process of perineural invasion. The abnormal expression of NGF and p75 may also be involved in this process and subsequently lead to a lower rate of curative surgery.